Nrf2-Mediated Antioxidant Response and Drug Efflux Transporters Upregulation as Possible Mechanisms of Resistance in Photodynamic Therapy of Cancers

Abstract

Olawale Razaq Ajuwon,1 Fleury Augustine Nsole-Biteghe,2 Jean Delacroix Ndong,3 Lester Merlin Davids,4 Basiru Olaitan Ajiboye,1 Bartholomew Brai,1 Fisayo Abraham Bamisaye,1 John Adeolu Falode,1 Ikenna Maximillian Odoh,1,5 Kabirat Iyabode Adegbite,6 Bosede Oluwasayo Adegoke,7 Monde Ntwasa,8 Sogolo Lucky Lebelo,8 Ademola Olabode Ayeleso8,9 1Department of Biochemistry, Federal University, Oye-Ekiti, Ekiti State, Nigeria; 2Department of Radiation Oncology and Biomedical Sciences, Cedars-Sinai Medical, Los Angeles, CA, USA; 3School of Arts and Science, Rutgers University, New Brunswick, NJ, 08901, USA; 4Graduate School of Business, University of Cape Town, Cape Town, South Africa; 5Medical Center, Federal University, Oye-Ekiti, Ekiti-State, Nigeria; 6Department of Environmental Health Science, College of Basic Medical and Health Sciences, Fountain University, Osogbo, Osun State, Nigeria; 7Department of Chemical Pathology, Ekiti State University, Ado-Ekiti, Ekiti State, Nigeria; 8Department of Life and Consumer Sciences, University of South Africa, Florida Park 1709, Roodeport, South Africa; 9Biochemistry Programme, Bowen University, Iwo, Osun State, NigeriaCorrespondence: Olawale Razaq Ajuwon, Department of Biochemistry, Federal University OyeEkiti, Ekiti State, Nigeria, Tel [phone], Email [email protected]: Photodynamic therapy (PDT) is a groundbreaking approach involving the induction of cytotoxic reactive oxygen species (ROS) within tumors through visible light activation of photosensitizers (PS) in the presence of molecular oxygen. This innovative therapy has demonstrated success in treating various cancers. While PDT proves highly effective in most solid tumors, there are indications that certain cancers exhibit resistance, and some initially responsive cancers may develop intrinsic or acquired resistance to PDT. The molecular mechanisms underlying this resistance are not fully understood. Recent evidence suggests that, akin to other traditional cancer treatments, the activation of survival pathways, such as the KEAP1/Nrf2 signaling pathway, is emerging as an important mechanism of post-PDT resistance in many cancers. This article explores the dual role of Nrf2, highlighting evidence linking aberrant Nrf2 expression to treatment resistance across a range of cancers. Additionally, it delves into the specific role of Nrf2 in the context of photodynamic therapy for cancers, emphasizing evidence that suggests Nrf2-mediated upregulation of antioxidant responses and induction of drug efflux transporters are potential mechanisms of resistance to PDT in diverse cancer types. Therefore, understanding the specific role(s) of Nrf2 in PDT resistance may pave the way for the development of more effective cancer treatments using PDT.Keywords: photodynamic therapy, oxidative stress, antioxidant response, tumor resistance, Nrf2

Keywords

• photodynamic therapy. oxidative stress. antioxidant response. tumor resistance. nrf2.